This invention relates to agents which inhibit type 2 methionine aminopeptidase (MetAP2), including novel ovalicin and fumagillin derivatives, and to the identification and use of such agents for treating and diagnosing diseases involving abnormal angiogenesis or immune reactions which result in pathology.
Angiogenesis is the process of new blood vessel formation. It has been shown to play a pivotal role in certain normal physiological reactions, e.g., wound healing, corpus luteum formation and embryonic development. It has also been reported to play a pivotal role in a variety of pathological conditions, e.g., tumors, diabetic retinopathy, inflammatory diseases and arteriosclerosis. For example, it has been reported that without access to sufficient vasculature, tumor growth is restrained as a result of widespread cell death.
Further, while immune reactions are required to protect animals from deleterious foreign antigens, certain immune reactions can result in pathological conditions, e.g., autoimmune diseases, allergies or tissue graft rejection.
Fumagillin and certain types of fumagillin analogs have been reported to exhibit anti-angiogenic activity, and ovalicin has been reported to exhibit anti-angiogenic and immunosuppressive activity.
There is a need for inhibitors which are more potent, less neurotoxic, more stable, and/or have longer serum half-lives.
It is an object of the invention to provide compounds which can be used in treating and/or diagnosing diseases involving abnormal angiogenesis or immune reactions resulting in pathology, which are potent, stable, have long serum half-lives, and/or which are polar, thereby being unable to penetrate the blood/brain barrier and thus resulting in low neurotoxicity.
It is yet another object of the invention to provide compounds which inhibit MetAP2 activity.
It is yet another object of the invention to provide compounds which inhibit endothelial cell proliferation.
It is yet another object of the invention to provide a method for identifying agents which are anti-angiogenic or immunosuppressive.
Still another object of the invention is to utilize MetAP2 to aid in identifying agents useful for the treatment and/or diagnosis of diseases involving abnormal angiogenesis or immune reactions which result in pathology.
In one aspect, the invention features a compound of the formula: 
and pharmaceutically acceptable salts thereof,
wherein
R1, R2, R3, R4, R5 and R6 can be the same or different from each other, and are hydrogen, alkyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido, lower alkoxy, a substituted alkanoyl group, a cyclic or aromatic cyclic group which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, a substituted aryl or aroyl group having at least one substituent selected from the group consisting of alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, amide, carbamoyl, carboxylic acid, carboxyl ester, carboxyl salt, hydroxyl and alkylthioether;
R7 is hydrogen or an hydroxy group; and
R8 is
(1) a subtituted alkyl, allyl or alkyne group; or
(2) a substituted alkoxyl or thioalkoxyl group, or methylene or ethylene alkoxyl or thioalkoxyl group, wherein the methylene or ethylene can be optionally substituted; or
(3) an aroyl group which can be optionally substituted with at least one substituent selected from the group consisting of alkyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, lower alkoxy, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxylic acid, carboxyl ester, carboxyl salt, alkyl or dialkylcarbamoyl, substituted ureido, vinyl, cyclic or aromatic cyclic groups which can be optionally substituted, or a heterocyclic or aromatic heterocyclic group which can be optionally substituted; or
(4) an aryl group which can be optionally substituted with at least one substituent selected from the group consisting of alkyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, lower alkoxy, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxylic acid, carboxyl ester, carboxyl salt, alkyl or dialkylcarbamoyl, substituted ureido, vinyl, cyclic or aromatic cyclic groups which can be optionally substituted, or a heterocyclic or aromatic heterocyclic group which can be optionally substituted; or
(5) an amino, alkylamino, dialkylamino, halogen, hydroxyl, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxyl, alkyl, dialkylcarbamoyl, ureido, vinyl, cyclic or aromatic cyclic groups which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, carboxylic acid, carboxyl ester, carboxyl salt; or
(6) an alkyl group which can be optionally substituted with N+P1P2P3Xxe2x88x92 or S+P1P2Xxe2x88x92, wherein P1, P2, and P3 can be the same or different and are each an optionally substituted hydrocarbon or heterocyclic group and Xxe2x88x92 is a counter anion; or
(7) 2-methyl-1-propenyl or an isobutyl group which can be optionally substituted with hydroxyl, carbamoyl, carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido, alky, lower alkoxy, a substituted alkanoyl group, a cyclic or aromatic cyclic group which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, a substituted aryl or aroyl group having at least one substituent selected from the group consisting of alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, amide, carbamoyl, carboxylic acid, carboxyl ester, carboxyl salt, hydroxyl or alkylthioether; or
(8) 2-methyl-1-propenyl or an isobutyl group which can be optionally substituted with N+P1P2P3Xxe2x88x92, S+P1P2Xxe2x88x92, wherein P1, P2 and P3 can be the same or different and are each an optionally substituted hydrocarbon or heterocyclic group and Xxe2x88x92 is a counter anion; or
(9) a benzenesulfonyl, methylsulfonyl or alkyl sufonyl group, with or without a methylene or ethylene substituent, or the corresponding amide or ester, which can be optionally substituted; or
(10) an alkoxycarbonyl or phenoxycarbonyl group with or without a methylene or ethylene substituent, which can be optionally substituted.
A preferred embodiment is a compound having the formula: 
Another aspect of the invention features a compound of the formula: 
and pharmaceutically acceptable salts thereof,
wherein
Z is an oxygen and can have R or S configuration;
R1, R2, R3, R4, R5 and R6 can be the same or different from each other and are hydrogen, alkyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido, lower alkoxy, a substituted alkanoyl group, a cyclic or aromatic cyclic group which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, a substituted aryl or aroyl group having at least one substituent selected from the group consisting of alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, amide, carbamoyl, carboxylic acid, carboxyl ester, carboxyl salt, hydroxyl and alkylthioether;
R7 and R8 can be the same or different from each other and are:
(1) hydrogen or a subtituted alkyl, allyl or alkyne group;
(2) a substituted alkoxyl or thioalkoxyl group, or methylene or ethylene alkoxyl or thioalkoxyl group, wherein the methylene or ethylene can be optionally substituted;
(3) an aroyl group which can be optionally substituted with at least one substituent selected from the group consisting of alkyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, lower alkoxy, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxylic acid, carboxyl ester, carboxyl salt, alkyl or dialkylcarbamoyl, substituted ureido, vinyl, cyclic or aromatic cyclic groups which can be optionally substituted, or a heterocyclic or aromatic heterocyclic group which can be optionally substituted; or
(4) an aryl group which can be optionally substituted with at least one substituent selected from the group consisting of alkyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, lower alkoxy, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxylic acid, carboxyl ester, carboxyl salt, alkyl or dialkylcarbamoyl, substituted ureido, vinyl, cyclic or aromatic cyclic groups which can be optionally substituted, or a heterocyclic or aromatic heterocyclic group which can be optionally substituted; or
(5) an amino, alkylamino, dialkylamino, halogen, hydroxyl, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxyl, alkyl, dialkylcarbamoyl, ureido, vinyl, cyclic or aromatic cyclic groups which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, carboxylic acid, carboxyl ester, carboxyl salt; or
(6) an alkyl group which can be optionally substituted with N+P1P2P3Xxe2x88x92, S+P1P2Xxe2x88x92, wherein P1, P2 and P3 can be the same or different and are each an optionally substituted hydrocarbon or heterocyclic group and Xxe2x88x92 is a counter anion; or
(7) 2-methyl-1-propenyl or an isobutyl group which can be optionally substituted with hydroxyl, carbamoyl, carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido, alky, lower alkoxy, a substituted alkanoyl group, a cyclic or aromatic cyclic group which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, a substituted aryl or aroyl group having at least one substituent selected from the group consisting of alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, amide, carbamoyl, carboxylic acid, carboxyl ester, carboxyl salt, hydroxyl or alkylthioether;
(8) 2-methyl-1-propenyl or an isobutyl group which can be optionally substituted with N+P1P2P3Xxe2x88x92, S+P1P2Xxe2x88x92, wherein P1, P2 and P3 can be the same or different and are each an optionally substituted hydrocarbon or heterocyclic group and Xxe2x88x92 is a counter anion; or
(9) a benzenesulfonyl, methylsulfonyl or alkyl sufonyl group, with or without a methylene or ethylene substituent, or the corresponding amide or ester, which can be optionally substituted; or
(10) an alkoxycarbonyl or phenoxycarbonyl group with or without a methylene or ethylene substituent, which can be optionally substituted.
Preferred embodiments are compounds having the formulas: 
or 
Another aspect of the invention is a compound of the formula: 
and pharmaceutically acceptable salts thereof,
wherein
A is a halogen, N+P1P2P3Xxe2x88x92 or S+P1P2Xxe2x88x92 wherein P1, P2 and P3 can be the same or different and are each an optionally substituted hydrocarbon or heterocyclic group and Xxe2x88x92 is a counter anion;
R1, R2, R3, R4, R5 and R6 can be the same or different from each other, and are hydrogen, alkyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido, lower alkoxy, a substituted alkanoyl group, a cyclic or aromatic cyclic group which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, a substituted aryl or aroyl group having at least one substituent selected from the group consisting of alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, amide, carbamoyl, carboxylic acid, carboxyl ester, carboxyl salt, hydroxyl and alkylthioether;
R7 is hydrogen or an hydroxy group; and
R8 is
(1) a subtituted alkyl, allyl or alkyne group; or
(2) a substituted alkoxyl or thioalkoxyl group, or methylene or ethylene alkoxyl or thioalkoxyl group, wherein the methylene or ethylene can be optionally substituted; or
(3) an aroyl group which can be optionally substituted with at least one substituent selected from the group consisting of alkyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, lower alkoxy, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxylic acid, carboxyl ester, carboxyl salt, alkyl or dialkylcarbamoyl, substituted ureido, vinyl, cyclic or aromatic cyclic groups which can be optionally substituted, or a heterocyclic or aromatic heterocyclic group which can be optionally substituted; or
(4) an aryl group which can be optionally substituted with at least one substituent selected from the group consisting of alkyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, lower alkoxy, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxylic acid, carboxyl ester, carboxyl salt, alkyl or dialkylcarbamoyl, substituted ureido, vinyl, cyclic or aromatic cyclic groups which can be optionally substituted, or a heterocyclic or aromatic heterocyclic group which can be optionally substituted; or
(5) an amino, alkylamino, dialkylamino, halgen, hydroxyl, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxyl, alkyl, dialkylcarbamoyl, ureido, vinyl, cyclic or aromatic cyclic groups which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, carboxylic acid, carboxyl ester or carboxyl salt; or
(6) 2-methyl-1-propenyl or an isobutyl group which can be optionally substituted with hydroxyl, carbamoyl, carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido, alky, lower alkoxy, a substituted alkanoyl group, a cyclic or aromatic cyclic group which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, a substituted aryl or aroyl group having at least one substituent selected from the group consisting of alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, amide, carbamoyl, carboxylic acid, carboxyl ester, carboxyl salt, hydroxyl or alkylthioether; or
(7) a benzenesulfonyl, methylsulfonyl or alkyl sufonyl group, with or without a methylene or ethylene substituent, or the corresponding amide or ester, which can be optionally substituted; or
(8) an alkoxycarbonyl or phenoxycarbonyl group with or without a methylene or ethylene substituent, which can be optionally substituted.
Another aspect of the invention is a compound of the formula: 
and pharmaceutically acceptable salts thereof,
wherein
A is a halogen, N+P1P2P3Xxe2x88x92 or S+P1P2Xxe2x88x92 wherein P1, P2 and P3 can be the same or different and are each an optionally substituted hydrocarbon or heterocyclic group and Xxe2x88x92 is a counter anion;
R1, R2, R3, R4, R5 and R6 can be the same or different from each other and are hydrogen, alkyl, aryl, halogen, hydroxyl, alkoxy, carbamoyl, carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido, lower alkoxy, a substituted alkanoyl group, a cyclic or aromatic cyclic group which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, a substituted aryl or aroyl group having at least one substituent selected from the group consisting of alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, amide, carbamoyl, carboxylic acid, carboxyl ester, carboxyl salt, hydroxyl and alkylthioether;
R7 is hydrogen or an hydroxy group; and
R8 is:
(1) hydrogen or a subtituted alkyl, allyl or alkyne group;
(2) a substituted alkoxyl or thioalkoxyl group, or methylene or ethylene alkoxyl or thioalkoxyl group, wherein the methylene or ethylene can be optionally substituted;
(3) an aroyl group which can be optionally substituted with at least one substituent selected from the group consisting of alkyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, lower alkoxy, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxylic acid, carboxyl ester, carboxyl salt, alkyl or dialkylcarbamoyl, substituted ureido, vinyl, cyclic or aromatic cyclic groups which can be optionally substituted, or a heterocyclic or aromatic heterocyclic group which can be optionally substituted; or
(4) an aryl group which can be optionally substituted with at least one substituent selected from the group consisting of alkyl, amino, alkylamino, dialkylamino, halogen, hydroxyl, lower alkoxy, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxylic acid, carboxyl ester, carboxyl salt, alkyl or dialkylcarbamoyl, substituted ureido, vinyl, cyclic or aromatic cyclic groups which can be optionally substituted, or a heterocyclic or aromatic heterocyclic group which can be optionally substituted; or
(5) an amino, alkylamino, dialkylamino, halogen, hydroxyl, cyano, amido, carbamoyl, thiocarbamoyl, carbonyldioxyl, carboxyl, alkyl, dialkylcarbamoyl, ureido, vinyl, cyclic or aromatic cyclic groups which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, carboxylic acid, carboxyl ester, carboxyl salt; or
(6) 2-methyl-1-propenyl or an isobutyl group which can be optionally substituted with hydroxyl, carbamoyl, carbonyldioxyl, thiohydroxyl, amino, alkylamino, dialkylamino, ureido, alkyl, lower alkoxy, a substituted alkanoyl group, a cyclic or aromatic cyclic group which can be optionally substituted, a heterocyclic or aromatic heterocyclic group which can be optionally substituted, a substituted aryl or aroyl group having at least one substituent selected from the group consisting of alkyl, amino, halogen, hydroxyl, lower alkoxy, cyano, amide, carbamoyl, carboxylic acid, carboxyl ester, carboxyl salt, hydroxyl or alkylthioether;
(7) a benzenesulfonyl, methylsulfonyl or alkyl sufonyl group, with or without a methylene or ethylene substituent, or the corresponding amide or ester, which can be optionally substituted; or
(8) an alkoxycarbonyl or phenoxycarbonyl group with or without a methylene or ethylene substituent, which can be optionally substituted.
Preferred embodiments are compounds having the formulas: 
Another aspect of the invention is a method for determining if an animal is at risk for a disease involving abnormal angiogenesis or an immune reaction resulting in pathology. An animal is provided. An aspect of MetAP2 metabolism or structure is evaluated in the animal. An abnormality in the aspect of MetAP2 metabolism or structure is diagnostic of being at risk for a disease involving abnormal angiogenesis or an immune reaction resulting in pathology.
Another aspect of the invention is a method for identifying an agent that is anti-angiogenic or immunosuppressive. A MetAP2 polypeptide is provided. An agent is provided. The agent is contacted with the MetAP2. The effect of the agent on an aspect of MetAP2 metabolism is evaluated, a change in the aspect of MetAP2 metabolism being indicative of the agent being anti-angiogenic or immunosuppressive.
In certain embodiments, the agent is an ovalicin analog, fumaginone or a fumaginone analog. In certain embodiments, the agent is a MetAP2 polypeptide or a biologically active fragment or analog thereof, a nucleic acid encoding MetAP2 polypeptide or a biologically active fragment or analog thereof, a nucleic acid encoding a MetAP2 regulatory sequence or a biologically active fragment or analog thereof, a binding molecule for MetAP2 polypeptide or MetAP2 nucleic acid, a mimetic of MetAP2 polypeptide or MetAP2 nucleic acid, an antibody for MetAP2 or a binding molecule of MetAP2, or an antisense nucleic acid for MetAP2 or a binding molecule for MetAP2.
Another aspect of the invention is a method for evaluating an agent for use in treating a disease involving abnormal angiogenesis or an immune reaction resulting in pathology. A test cell, cell-free system or animal is provided. An agent is provided. The agent is administered to the test cell, cell-free system or animal in a therapeutically effective amount. The effect of the agent on an aspect of MetAP2 metabolism is evaluated. A change in the aspect of MetAP2 metabolism is indicative of the usefulness of the agent in treating a disease involving abnormal angiogenesis or in inhibiting an immune reaction resulting in pathology.
Another aspect of the invention is a method for evaluating a candidate anti-angiogenic or immunosuppressive agent for the ability to alter the binding of MetAP2 polypeptide to a binding molecule. An agent is provided. A MetAP2 polypeptide is provided. A binding molecule is provided. The agent, MetAP2 polypeptide and binding molecule are combined. The formation of a complex comprising the MetAP2 polypeptide and binding molecule is detected. An alteration in the formation of the complex in the presence of the agent as compared to in the absence of the agent is indicative of the agent altering the binding of the MetAP2 polypeptide to the binding molecule.
Another aspect of the invention is a method for evaluating a candidate anti-angiogenic or immunsuppressive agent for the ability to bind to MetAP2 polypeptide. An agent is provided. A MetAP2 polypeptide is provided. The agent is contacted with the MetAP2 polypeptide. The ability of the agent to bind to the MetAP2 polypeptide is evaluated.
Another aspect of the invention is a method for evaluating a candidate anti-angiogenic or immunosuppressive agent for the ability to bind to a nucleic acid encoding a MetAP2 regulatory sequence. An agent is provided. A nucleic acid encoding a MetAP2 regulatory sequence is provided. The agent is contacted with the nucleic acid. The ability of the agent to bind to the nucleic acid is evaluated.
Another aspect of the invention is a method for treating a cell having an abnormality in metabolism or structure of MetAP2. A cell having an abnormality in structure or metabolism of MetAP2 is provided. An agent, e.g., an ovalicin analog, fumaginone or a fumaginone analog, capable of altering an aspect of MetAP2 metabolism or structure is provided. The agent is administered to the cell in a therapeutically effective amount such that treatment of the cell occurs.
In certain embodiments, the agents are compounds having formulas I, II, III or IV, or pharmaceutically acceptable salts thereof, described herein. In certain preferred embodiments, the agents are compounds having formulas 1, 2, 3, 4, 5 or 6, or pharmaceutically acceptable salts thereof, described herein. In certain embodiments, the agent is a MetAP2 polypeptide or a biologically active fragment or analog thereof, a nucleic acid encoding MetAP2 polypeptide or a biologically active fragment or analog thereof, a nucleic acid encoding a biologically active fragment or analog thereof, a binding molecule for MetAP2 polypeptide or MetAP2 nucleic acid, a mimetic of MetAP2 polypeptide or MetAP2 nucleic acid, an antibody for MetAP2 or a binding molecule of MetAP2, or an antisense nucleic acid for MetAP2 or a binding molecule for MetAP2.
Another aspect of the invention is a method for treating abnormal angiogenesis in an animal. An animal in need of treatment for abnormal angiogenesis is provided. An agent, e.g., an ovalicin analog, fumaginone or a fumaginone analog, capable of altering an aspect of MetAP2 metabolism or structure is provided. The agent is administered to the animal in a therapeutically effective amount such that treatment of the abnormal angiogenesis occurs.
Another aspect of the invention is a method for treating an animal at risk for abnormal angiogenesis. An animal at risk for abnormal angiogenesis is provided. An agent, e.g., an ovalicin analog, fumaginone or a fumaginone analog, capable of altering an aspect of MetAP2 metabolism or structure is provided. The agent is administered to the animal in a therapeutically effective amount such that treatment of the animal occurs. Being at risk for abnormal angiogenesis can result from, e.g., a familial history of abnormal angiogenesis, phenotypic symptoms which predispose to abnormal angiogenesis, or a genotype which predisposes to abnormal angiogenesis.
Another aspect of the invention is a method for treating a tumor in an animal. An animal in need of treatment for a tumor is provided. An agent, e.g., an ovalicin analog, fumaginone or a fumaginone analog, capable of altering an aspect of MetAP2 metabolism or structure is provided. The agent is administered to the animal in a therapeutically effective amount such that treatment of the tumor occurs.
Another aspect of the invention is a method for treating an immune reaction which results in pathology in an animal. An animal in need of treatment for an immune reaction which results in pathology is provided. An agent, e.g., an ovalicin analog, fumaginone or a fumaginone analog, capable of altering an aspect of MetAP2 metabolism or structure, is provided. The agent is administered to the animal in a therapeutically effective amount such that treatment of the immune reaction occurs.
Another aspect of the invention is a method for treating an animal at risk for an immune reaction which results in pathology. An animal in need of treatment for an immune reaction which results in pathology is provided. An agent, e.g., an ovalicin analog, fumaginone or a fumaginone analog, capable of altering an aspect of MetAP2 metabolism or structure, is provided. The agent is administered to said animal in a therapeutically effective amount such that treatment of the animal occurs. Being at risk for an immune reaction which results in pathology can result from, e.g., a familial history of such reactions, phenotypic symptoms which predispose to such reactions, or a genotype which predisposes to such reactions.
Another aspect of the invention is a pharmaceutical composition for treating abnormal angiogenesis in an animal comprising a therapeutically effective amount of an agent, e.g., an ovalicin analog, fumaginone or a fumaginone analog, capable of altering an aspect of MetAP2 metabolism or structure in the animal so as to result in treatment of the abnormal angiogenesis, and a pharmaceutically acceptable carrier.
Yet another aspect of the invention is a pharmaceutical composition for treating an immune reaction which results in pathology in an animal comprising a therapeutically effective amount of an agent, e.g., an ovalicin analog, fumaginone or a fumaginone analog, capable of altering an aspect of MetAP2 metabolism or structure in the animal so as to result in treatment of the immune reaction which results in pathology, and a pharmaceutically acceptable carrier.
The above and other features, objects and advantages of the present invention will be better understood by a reading of the following specification in conjunction with the drawings.